Alzheimer's disease (AD) and the related Frontotemporal Dementia (FTD) together affect ~5.4 million Americans and result in nearly $200 billion annually in healthcare and long-term patient care costs. Yet despite this massive health problem, large gaps remain in our understanding of these diseases. We have uncovered a novel epigenetic mechanism in mice that functions in the maintenance of differentiated hippocampus neurons, and we have linked this mechanism to AD and FTD. We hypothesize that this epigenetic mechanism is inhibited by pathological protein aggregates in aging adults, resulting in inappropriate transcription (including reactivation of stem cell transcription) and neuronal cell death. In this proposal, we will investigate this new epigenetic pathway in our mouse model as well as in human patient's samples. In addition, because (unlike other dementia models) our mouse model exhibits massive hippocampus neuronal cell death, we will combine our mouse model with other mouse models to identify common mechanisms of neuronal cell death, as occur in neurodegeneration. This proposal is significant in that it mechanistically bridges the gap between pathological aggregates observed in AD and FTD cases and the neuronal cell death that underlies these dementias. Based on these studies, it may be possible to therapeutically target this new pathway in AD and FTD patients. These studies will also investigate common mechanisms of neuronal cell death that could serve as additional potential therapeutic targets. As a result, this proposal is directly responsive to the National Plan to Address Alzheimer's Disease priority; to investigate new pathways that can be targeted for treatment. In addition, this proposal is innovative because it links a novel epigeneti mechanism that is required to maintain differentiated cell fates to AD and FTD. As a result, these studies will also significantly impact our understanding of basic developmental biology and stem cell biology.